Integrins comprise a family of cell adhesion receptors composed of alpha/beta heterodimeric subunits that provide a functional and structural bridge between the extracellular matrix and intracellular signaling molecules (Hynes R O, 1992). Expression of the αvβ6 integrin in ovarian cancers may contribute to the invasive potential of ovarian cancers (Ahmed N. et al., 2001; Ahmed N. et al., 2002) and expression of the αvβ6 integrin in colon cancer has been identified as an independent prognostic indicator for worse outcome in patients suffering from this disease (Bates R C. et al., 2005). The 15 mer amino acid sequence RSKAKWQTGTNPLYR (SEQ ID No. 1) located within the cytoplasmic tail of the β6 integrin subunit binds to extracellular signal-regulated kinase 2 (ERK2) and it has been proposed that this contributes to tumor growth (Ahmed N. et al., 2002).
The non-naturally occurring peptide RSKAKNPLYR (SEQ ID No. 2) derived from the β6 binding sequence has also been reported to inhibit cancer cell growth, which may be due at least in part to the inhibition of c-Src activity by the peptide (Agrez M V. et al., 2011).
Notably, within this sequence there is a NPxY/F (SEQ ID No. 3) motif common to β integrin cytoplasmic domains that forms part of a canonical recognition sequence for phosphotyrosine-binding (PTB) domains. Indeed, the NPxY/F (SEQ ID No. 3) motif is present in the amino acid sequences derived from the β2, β3 and β5 integrin subunits which correspond to the RSKAKNPLYR (SEQ ID No. 2) peptide, all of which have also been shown to be anti-cancer peptides and bind ERK2 (see International Patent Application WO 2005/037308) reflecting the apparent importance of the motif. PTB domains are protein modules present in a wide variety of signaling and cytoskeletal proteins. It has, for example, been suggested that phosphorylation of the tyrosine (Y) residue in the NPxY (SEQ ID No. 4) motif may represent a mode of regulating integrin interactions with other proteins at the cytoplasmic face of the plasma membrane (Takada Y. et al., 2007). The fundamental role of the highly conserved NPxY (SEQ ID No. 4) motif in regulating integrin-mediated function has been emphasized by Filardo and colleagues who showed that the NPxY (SEQ ID No. 4) motif within the β3 cytoplasmic tail is essential for αvβ3-dependent post-ligand binding events involved in cell migration and the metastatic phenotype of melanoma cells (Filardo E J, 1995).